PROJECT SUMMARY Although tobacco smoking rates continue to decrease, cigarette smoking remains the leading cause of preventable disease and death in the United States and few tobacco users achieve sustained abstinence, underscoring the need for alternative treatments. The endocannabinoid system can modulate the reinforcing effects of nicotine and may be a target for development of pharmacotherapies for tobacco cessation. The CB1 receptor inverse agonist/antagonist rimonabant has demonstrated efficacy in increasing tobacco abstinence rates in clinical trials, though it was abandoned as a viable medication due to adverse psychiatric side effects. Compounds that have similar pharmacology to rimonabant, but without the adverse psychiatric side effect profile may be efficacious for tobacco cessation. Cannabidiol (CBD) is a naturally occurring constituent of the cannabis plant that has been well tolerated in clinical studies and has low abuse liability. CBD has demonstrated anxiolytic, antipsychotic, and antidepressant effects, and can reduce appetite, suggesting that it may reduce known nicotine withdrawal symptoms associated with relapse. One clinical study provided initial evidence that CBD may be useful to promote tobacco cessation, however, the mechanism by which smoking was reduced is not clear and appropriate dosing remains unknown. This proposed study will apply a rigorous methodological approach with systematic dose administration and biochemical verification of smoking abstinence to evaluate CBD as a potential pharmacotherapy for tobacco cessation. A double-blind, within- subject, double-crossover design will be used to compare the effect of twice-daily oral CBD and matched placebo on short-term tobacco abstinence, and explore potential mechanisms underlying the effect of CBD on tobacco withdrawal, negative affect, and reinforcement. Results from this study will provide initial data to determine whether CBD increases short-term tobacco abstinence, and will also evaluate potential mechanisms underlying CBD?s efficacy as a treatment for tobacco cessation (e.g. tobacco withdrawal, reinforcement) which has implications for improving understanding the specific role of the endocannabinoid system in modulating the addictive properties of nicotine. This study will support several future studies. A positive signal would support a subsequent R01 to conduct a series of studies to determine a full dose-effect profile and further identify mechanisms underlying CBD?s effect on tobacco cessation outcomes, and would also provide a strong rationale for conduct of larger phase II and III clinical trials to evaluate the efficacy of CBD to improve sustained tobacco abstinence in larger sample sizes.